Abstract Oral cancer affects nearly 300,000 Americans each year and is a serious health concern due to its poor prognosis and high recurrence rate. Moreover, the worldwide tobacco epidemic is leading to thousands of new cases of oral cancer being diagnosed each year. Targeting preventive strategies for those at highest risk for oral cancer due to tobacco exposure is thus a high priority. Our ultimate goal is to employ a food-based cancer preventive strategy for high-risk populations that allows excellent long-term adherence and efficacy. The oral cavity is an open microbial ecosystem that plays host to over 700 species of bacteria that form healthcompatible communities called biofilms. We have previously demonstrated that these biofilms are rapidly enriched for pathogenic bacteria in smokers, resulting in an early hyper-inflammatory response. Furthermore, smoking cessation reverses this pathogenic bacterial recolonization, demonstrating that smoking has a direct effect on the oral microbiome and may increase the risk for oral carcinogenic processes by disturbing normal host-bacterial interactions. Therefore, our central hypothesis is that a critical bi-directional interaction exists between oral bacteria and phytochemical-rich black raspberry food products, which ultimately results in attenuation of inflammation and amelioration of disease. First, we will determine the effect of black raspberry phytochemicals (BRBs) on community dynamics within oral biofilms by combining a longitudinal clinical study design and a novel BRB delivery system (BRB nectar) with the resolution provided by shotgun metagenomic sequencing and computational bioinformatics. Next, we will examine the effect of oral bacterial communities on metabolism of BRBs in current and never smokers. Targeted HPLC-MS/MS analysis will be used to identify known phenolics and metabolites, while untargeted UHPLC Q-TOF metabolome analysis will identify novel compounds. Finally, we will evaluate the efficacy of BRBs and their metabolites in reversing the effect of smoking on oral host-microbial interactions by combining a longitudinal clinical study design with a novel, high-throughput ?dual RNA-Seq? methodology to simultaneously quantify both oral bacterial and oral mucosal transcriptome changes before and after exposure to BRB nectar. Following the successful completion of these Specific Aims, we will demonstrate for the first time the ability of BRBs to mitigate pathogenic metabolic process and gene expression patterns induced by cigarette smoke in a manner that supports oral carcinogenesis prevention strategies.